Method of treating rheumatoid arthritis with histidine

ABSTRACT

THE ADMINISTRATION OF THE AMINO ACID HISIDINE OR NONTOXIC SALTS OF THAT ACID IS USEFUL IN THE ALLEVIATION OF SYMPTOMS AND EFFECTS RELATED TO RHEUMATOID ARTHRITIS.

United States Patent US. Cl. 424-319 Claims ABSTRACT OF THE DISCLOSUREThe administration of the amino acid histidine or nontoxic salts of thatacid is useful in the alleviation of symptoms and effects related torheumatoid arthritis.

The invention described herein was made in the course of, or under, agrant from the U8. Public Health Service, Department of Health,Education, and Welfare.

This invention relates to a method for relieving symptoms and effectsassociated with rheumatoid arthritis. More particularly, this inventionis concerned with a method of relieving such symptoms and effects by theadministration of effective dosages of histidine or non-toxic histidinesalts.

Histidine (also known as alpha-amino-4(or 5 )-imidazolepropionic acid orglyoxaline-S-alanine) and its derivatives are known in the art.Histidine hydrochloride, in particular, has been employed as atherapeutic agent for the treatment of peptic ulcers although it is nolonger recommended for that purpose.

It has now been discovered that the use of histidine or non-toxic saltsof histidine, preferably L-histidine, L-histidine monohydrochloridemonohydrate or compositions containing these compounds as activeingredients are effective in the treatment of rheumatoid arthritis. Thetreatment of patients with these compositions results in the alleviationof any or all of the manifestations of this disease including pain,tenderness, stiffness, swelling, red ness, warmth, deformity andlimitation of motion of any and all joints characteristically involvedin this condition. In addition the administration of histidine and itsderivatives also results in a lessening of fatigue, fever, malaise,anorexia, Weight loss, muscle atrophy, anemia, abnormality of theerythrocyte sedimentation rate, concentration of rheumatoid factor inthe blood, and other manifestations of rheumatoid arthritis.

The compositions of this invention may be prepared in any manner knownin the art. For example, it may be produced by isolation from proteinhydrolysates. It will be understood by those persons skilled in the artthat the histidine compounds employed in the novel treatment of thisinvention may be combined with any compatible pharmaceutical carrier orvehicle and, in addition, can be combined with other compatible activecompounds such as analgesics and anti-inflammatory substances.

The preferred method of treatment with the histidine compounds disclosedherein comprises the oral administration of the compound in amountsranging from 0.375 to 8.0 grams or more per day, preferably 4.0grams/day. The dosage may vary widely within this range depending uponsuch facts as the size of the patient and the severity of the patientscondition. The number, amount and timing of daily dosages is notcritical and up to 5.0 grams of the active ingredient may be given atone time, although spaced, smaller dosages are preferred. Moreover thereis no apparent limit to the duration of treatment by this method.

The administration of the composition is susceptible to any one of theconventional pharmaceutical forms such as tablets, drages,gelatin-coated pills and preferably gelatin capsules. It may also beformulated in liquid form.

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For convenience, individual doses containing 100 to 500 mg. of activesubstance are preferred. Although oral administration is preferred, theactive ingredient used in the treatment may also be dispensed as asuppository or as a sterile injectible liquid in similar individualdoses.

The efficacy of the treatment of the invention has been determinedclinically in a study performed on 9 men and 50 women with definite orclassical rheumatoid arthritis. The patients had an average age of 51years and the average duration of the disease was 8 years. Rheumatoidfactor was present in 89% of the patients.

Prior to actual treatment with the histidine compositions, each patientwas treated for a varying period of time with a placebo. Placebocapsules contained Cream of Rice cereal. Patients were not advised whenthe placebo period ended in order to prevent the psychological effect oftreatment from interfering with the evaluation. Half of the patientsreceived placebo for at least 4 months and a histidine composition forat least 6 months. Eight patients received placebo for 11 months, and 13patients have so far received histidine for 10 months. The length of theplacebo period was not uniform primarily because the placebo periodelected was one month when the study began, then increased to 4 months,and then to 6 months in some and 12 months in others when it becameapparent that a longer placebo period would give more credibility to theresults.

The length of the treatment period was not uniform because the study isongoing and the patients did not all begin taking histidine at the sametime. Treatment comprised oral administration of L-histidine orL-histidine monohydrochloride monohydrate in 375 milligram capsules,taken 1 to 4 at a time, at regular intervals throughout the day in adaily dose of 1 to 8 grams. The average dose was 3 grams/day.

During both the placebo and actual treatment periods, patients wereevaluated at two to three week intervals and the following informationwas obtained on each evaluation:

(a) Time of day;

(b) Dose of either histidine or placebo taken by determining number ofcapsules given and number remain- (C) Grip strengthtaken three times ineach hand with a mercury manometer and standard bandage blood pressurecuff, folded according to the procedure used by the Cooperating ClinicsCommittee of the American Rheumatism Association and inflated to 20 mm.Hg;

(d) Time to walk 25 feet and 50 feet;

(e) Duration of morning stiffness;

(f) Dose of aspirin, prednisone, Darvon and any other drugs taken by thepatient;

(g) Assessment of patients general status as reported by the patient.

At one to two month intervals, blood was obtained for Westergrenerythrocyte sedimentation rate, hematocrit, and serum histidine; serumremaining was stored at 20 C. White blood count, liver and kidneyfunction tests, serum albumin and globulin, serum cholesterol, bloodsugar, other blood tests and urinalysis were done at less frequentintervals.

During the study, patients and the other physicians caring for thepatient were allowed to change the patients therapy (other thanadministration of histidine) as they thought fit, based on the patientscondition. 'During the placebo period that preceded the administrationof histidine, the patients took the following drugs (average dose):aspirin, 2.4 gm./day (three patients took no aspirin); prednisone, 9.7mg./day in 24 patients; dextropropoxyphene (Darvon), 182 mg./day in 24patients; phenylbutazone, mg./day in 1 patient; indomethacin,

52 mg./day in patients, and maintenance gold in 1 patient. No patientsreceived chloroquine or immunosuppressive agents.

The information obtained from all the patients in the study was pooledand statistically evaluated. For each month of the placebo period, nogrip, walk, or sedimentation rate was statistically significantlydilferent from the corresponding value at the end of the placebo period.During the histidine period, however, the results were quite different.For every month of the histidine period, the values for grip strength,walking time, and the sedimentation rate were all statisticallysignificantly better than the corresponding values obtained at the endof the placebo period.

During the 11-month placebo period, there was a slight but statisticallysignificant deterioration in grip strength but no consistent trend inwalking time or sedimentation rate. During the period of histidineadministration not only was improvement apparent but the degree ofimprovement was statistically significantly correlated with the month oftherapy, the maximum improvement occurring at the end of the histidineperiod. After months of histidine administration, the grip strength was30 mm. Hg stronger, the walking speed was 6 seconds per 50 feet faster,and the sedimentation rate was 18 mm. (Westergren) lower than the meanvalue for the placebo period.

In 25 patients, less aspirin was required during histidineadministration than during the placebo period. In these 25 patients, theaverage decrease in the dose of aspirin was 1.6 grams per day. Threepatients required more aspirin after histidine; in each, the increasewas 0.3 gram per day. In all the other patients, the aspirin dose didnot change. Six of the 24 patients receiving prednisone required less ofthis drug after histidine; the average decrease in dose was 4 milligramsper day; no patient required more prednisone. Six patients reduced theirdose of Darvon after histidine; the average decrease in dose was 65milligrams per day; no patient increased the dose. The one patientreceiving phenylbutazone discontinued this drug after histidinetreatment. One patient reduced the dose of indomethacin from 150milligrams per day to zero; one patient took indomethacin (25 milligramsper day) only during the histidine period; and in 4 patients the dose ofindocin remained unchanged. No other changes in the dose ofanti-inflammatory drugs took place during the study, nor was there anychange in any patient in physical therapy during the study. Thus, itdoes not appear that the improvement noted during the histidine periodof this study was due to any increase in the dose of anyanti-inflammatory drug except histidine. On the contrary, improvementappears to have taken place in spite of a significant reduction in thedosage of other drugs.

Anemia (i.e. hematocrit less than 37% in a woman or less than 40% in aman) was noted in patients before histidine treatment, but in only 1patient after histidine treatment. Morning stiffness decreased in 25patients and increased in 4 patients after treatment with histidine; inthe remaining patients there was no change in morning stilfness.

In 23 patients, placebo was given after the patients had finished acourse of histidine therapy. Nineteen of these 23 patients showedevidence of deterioration in one 4 or more of the parameters measured,i.e. grip, walk, and sedimentation rate. In those patients that showeddeterioration, the average period of time between the cessation ofhistidine therapy and the onset of deterioration was 5 months.

Table 1 compares the results obtained after the administration ofhistidine for six months with the results obtained after an equal periodof placebo, gold or hydroxychloroquine as noted in three other studies,a gold study by the Cooperating Clinics Committee of the AmericanRheumatism Association, a hydroxychloroquine study by the same group;and a gold study by the Empire Rheumatism Council. The results obtainedwith histidine are significantly better than the results obtained withplacebo in all three studies and approximately equal to the resultsobtained with gold in the two gold studies. The improvement found withhistidine administration appears to be somewhat better than theimprovement found with hydroxychloroquine.

1 Not done.

No side etfects of histidine were observed at any time throughout thisstudy. Specifically, patients did not complain of the taste of thehistidine, nausea, diarrhea, epigastric discomfort or anorexia anddeveloped no rashes, abnormalities of renal or hepatic function, anemiaor leukopenia, that could be attributed to the administra tion ofhistidine.

The results of the clinical studies clearly establish that theadministration of histidine is effective in alleviating symptoms ofrheumatoid arthritis.

What is claimed is:

1. A method of treating symptoms and effects of rheumatoid arthritis inhumans comprising the human inges tion of a compound selected from thegroup consisting of histidine and a nontoxic salt of histidine in anamount sufiicient to alleviate said symptoms.

2. The method of claim 1 wherein said compound is L-histidine.

3. The method of claim 1 wherein said compound is L-histidinemonohydrochloride monohydrate.

4. The method of claim 1 wherein the daily amount of ingestion of saidcompound is 0.375 to 8.0 grams.

5. The method of claim 1 wherein said compound is orally ingested.

References Cited Chem. Abst., 59, 3199-b (1963).

STANLEY J. FRIEDMAN, Primary Examiner

